Structure-Guided Identification of Black Cohosh (Actaea racemosa) Triterpenoids with In Vitro Activity against Multiple Myeloma

Abstract

Black cohosh is a well-established medicinal plant and preparations of its rootstock are used for the treatment of mild climacteric complaints. The compounds considered responsible for the therapeutic effect are triterpene glycosides, characterized by a cycloartane scaffold and a pentose moiety. Because some of these triterpenoids were found to exhibit relevant cytotoxic effects against human breast cancer cells, we decided to investigate their activity on multiple myeloma cell lines NCI-H929, OPM-2, and U266. In a systematic approach, we initially tested three known cytotoxic compounds of three different triterpenoid types, revealing the cimigenol-type triterpenoid as the most active constituent. In a second round, seven naturally occurring cimigenol derivatives were compared with respect to their sugar moiety and their substitution pattern at position C-25, leading to 25-O-methylcimigenol-3-O-α-L-arabinopyranoside as the most potent candidate. Interestingly, not only the methyl group at position C-25 increased the cytotoxic effect but also the arabinose moiety at position C-3 had an impact on the activity. The variety of cimigenol derivatives, moreover, allowed a detailed discussion of their structure-activity relationships, not only for their effect on multiple myeloma cells but also with regard to previous studies on the cytotoxicity of black cohosh triterpenoids.

Cytotoxic constituents and a new hydroxycinnamic acid derivative from Leontodon saxatilis (Asteraceae, Cichorieae)

“…[25][26][27] However, against myeloma cell lines so far only caffeic acid phenethyl ester (CAPE) was found to induce apoptosis, which is achieved by activation of caspase-3 and corresponding cleavage of poly(ADP-ribose)polymerase. 28 The observed activity of cichoric acid (13) in our study thus is reasonable. In contrast to the other isolated hydroxycinnamic acid derivatives (1-3, 5, 6), cichoric acid is lacking the quinic acid ring and same as CAPE shows a closer connection of the two arylalkylic substructures than dicaffeoylquinic acids 5 and 6.…”

“…Interestingly, especially for compound 10, stroma cells appeared to be more susceptible than PBMC, however, myeloma cells were more affected than stroma cells. The same accounts for cichoric acid (13), which showed higher effects against all three myeloma cell lines than against healthy PBMC and HS5 cells. The most cytotoxic substances in this screen were apigenin (14) and luteolin (15).…”

“…However, methyl 3,5dicaffeoylquinate (5) and the new natural product 5-feruoyl-2ahydroxyquinic acid (2) at least exhibited weak to moderate effects at the highest concentration tested. In contrast, cichoric acid (13) was decreasing the viability of the tested cell lines at all measured concentrations. Here, the strongest effect was observed against OPM-2 cells, where viability was decreased by approximately 50%.…”

“…HR-ESI-MS spectra were recorded on a Q-Exactive Plus spectrometer (Thermo Scientic, Bremen, Germany) and optical rotation was measured on a PerkinElmer 241 Polarimeter (PerkinElmer, Rodgau, Germany). NMR spectra were recorded on a Bruker Avance III 400 NMR spectrometer operating at 400 MHz for the proton channel and 100 MHz for the 13 C channel with a 5 mm PABBO broad band probe with a z gradient unit at 293 K (Bruker BioSpin GmbH, Rheinstetten, Germany). Reference values were 3.31 ( 1 H) and 49.15 ppm ( 13 C) for methanol as well as 2.50 ( 1 H) and 39.51 ppm ( 13 C) for DMSO, respectively.…”

“…Moreover, we discovered activity for a crude extract against two myeloma cell lines in a cytotoxicity screening, which also led to the previously reported identication of antimyeloma constituents in Turnera diffusa and Actaea racemosa. 12,13 Multiple myeloma is a plasma cell malignancy, which is mainly restricted to the bone marrow. 14 The current standard treatment includes immunomodulatory drugs and proteasome inhibitors, such as bortezomib.…”